WO2015165340A1 - Dérivé de thiadiazolidine anti-entérovirus 71 - Google Patents

Dérivé de thiadiazolidine anti-entérovirus 71 Download PDF

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WO2015165340A1
WO2015165340A1 PCT/CN2015/077043 CN2015077043W WO2015165340A1 WO 2015165340 A1 WO2015165340 A1 WO 2015165340A1 CN 2015077043 W CN2015077043 W CN 2015077043W WO 2015165340 A1 WO2015165340 A1 WO 2015165340A1
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group
etoac
mmol
nmr
oxy
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PCT/CN2015/077043
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English (en)
Chinese (zh)
Inventor
李鹏
贺海鹰
李宁
黎健
陈曙辉
杨百灵
沈旺
肖伟
Original Assignee
南京明德新药研发股份有限公司
江苏康缘药业股份有限公司
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Priority claimed from CN201410543064.6A external-priority patent/CN105085512A/zh
Application filed by 南京明德新药研发股份有限公司, 江苏康缘药业股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to US15/307,710 priority Critical patent/US9988361B2/en
Priority to ES15786304T priority patent/ES2841418T3/es
Priority to CN201580011272.4A priority patent/CN106661009B/zh
Priority to JP2016565011A priority patent/JP6389531B2/ja
Priority to KR1020187016595A priority patent/KR101957178B1/ko
Priority to SG11201608710TA priority patent/SG11201608710TA/en
Priority to KR1020167033211A priority patent/KR20160147010A/ko
Priority to DK15786304.4T priority patent/DK3138840T3/da
Priority to EP15786304.4A priority patent/EP3138840B1/fr
Publication of WO2015165340A1 publication Critical patent/WO2015165340A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel anti-enteric virus 71 (EV71) 1,2,5-thiadiazolidine-1,1-dioxide derivative or a pharmaceutically acceptable salt thereof, in particular to the formula (II) A compound or a pharmaceutically acceptable salt thereof.
  • Enterovirus 71 belongs to the family of small RNA viruses and is one of the most common sources of hand, foot and mouth disease. It can also cause a variety of neurological-related diseases such as herpes pharyngitis, aseptic meningitis, encephalitis, and polio-like paralytic diseases, which can be accompanied by severe central nervous system complications or neuroinflammation. Pulmonary Edema.
  • Hand, foot and mouth disease has the characteristics of high epidemic intensity, strong contagiousness and complicated transmission route. So far, there is no specific anti-enteric virus type 71 drug.
  • the present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
  • R 3 is selected from a 5-membered heterocyclic ring optionally substituted by R 01 , a C 6- 12 aryl group, a C 6- 12 aralkyl group, a C 5-12 heteroaryl ring or a C 5-12 heteroarylalkyl group;
  • L 2 are independently selected from
  • n 1 , m 2 are each independently selected from 0, 1 , 2 , 3, 4, 5 or 6;
  • R 4 is selected from a 5- to 14-membered cyclic hydrocarbon group or a heterocyclic hydrocarbon group
  • R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl group optionally substituted by R 01 or a heteroalkyl group, a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl;
  • R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, R 02 ;
  • R 02 is selected from C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1 -10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl;
  • R d3 - d7 are each independently selected from H, R 03 ;
  • R 03 is selected from C 1-10 alkyl, C 1-10 alkyl acyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 a cycloalkyl group, a C 3-10 cycloalkyl acyl group, a C 3-10 cycloalkoxycarbonyl group, a C 3-10 cycloalkylsulfonyl group, a C 3-10 cycloalkylsulfinyl group;
  • R 02 and R 03 are optionally substituted by R 001 ;
  • R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, A Base, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;
  • R 01 , R 001 , hetero atom or hetero atomic group is independently selected from 0, 1, 2 or 3;
  • R d1 and R d2 are linked to each other to form a 3 or 4 membered carbocyclic or heterocyclic ring.
  • R 3 is selected from a 5 to 6 membered aryl or heteroaryl group which is optionally substituted.
  • R 3 is selected from R 01 is optionally substituted pyridyl, phenyl, furanyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, thienyl, R 01 is In the above definition, the number of R 01 is selected from 0, 1, 2 or 3.
  • R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, Me,
  • R 3 is selected from the group consisting of
  • L 2 is selected from m 3 is 0, 1, or 2, and other variables are as defined above.
  • L 2 is selected from the group consisting of
  • R 4 is selected from T 4-7 are each independently selected from N or C(R t ),
  • n 2 is selected from 0, 1, 2 or 3,
  • n 3 is selected from 0, 1 or 2
  • R 5 , R 6 , R 7 , R t , R d1 , R d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or selected from the group consisting of a C 1-10 alkyl or heteroalkyl group substituted by R 01 , a C 3-10 cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group ,
  • R 4 is selected from X 3 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
  • R 5-7 are each independently selected from among them:
  • T 1-3 are each independently selected from N or C(R t );
  • R 8 , R 9 , R t are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or C 1-10 selected from R 1 , optionally substituted by R 01 .
  • R 10 is selected from F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, or a C 1-10 alkyl or heteroalkyl group optionally substituted by R 01 , C 3-10 a cycloalkyl or heterocycloalkyl group, a C 1-10 alkyl or heteroalkyl group substituted by a C 3-10 cycloalkyl or heterocycloalkyl group.
  • R 5-9 , R 01 , R t are each independently selected from F, Cl, Br, CF 3 , -C(C 2 H 5 )-, -C(OC 2 H 5 )-, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,
  • R 4 is selected from the group consisting of
  • the invention is selected from the group consisting of:
  • C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ;
  • C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
  • C 1-12 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by the addition of these compounds in free acid or base form in water or an organic solvent or a mixture of the two.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or "therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent means a drug that is non-toxic but achieves the desired effect. Or a sufficient amount of the agent.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof.
  • Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.
  • R', R", R"', R"" and R""' are each independently preferred Hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkoxy, sulphur Alkoxy group or aralkyl group.
  • each R group is independently selected as if present Each of these groups of more than one R', R", R"', R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they may be bonded to the nitrogen The atoms combine to form a 5-, 6- or 7-membered ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom, which It may be saturated, partially unsaturated or unsaturated (aromatic) which comprises a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above is hetero
  • the ring may be fused to a benzene ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (preferably 1 to 3 rings) which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridyl) Methyl or the like, including those wherein a carbon atom such as a methylene group has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl Wait.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.
  • Example 4A (5 g, 28.9 mmol) was dissolved in a mixed solvent of dichloromethane and N,N-dimethylformamide (50 ml / 5 ml), and the mixture was added dropwise to the mixed solution at 15 ° C. The sulfone (60 ml) was then raised to 40 ° C for 16 hours. After cooling to room temperature, pour ice water (200 ml), add 1 mol of aqueous sodium hydroxide solution to adjust the pH to 10, extract the aqueous layer with ethyl acetate (100 ml ⁇ 6), and combine the organic layer with brine (50 ml), EtOAc (EtOAc m.
  • EtOAc EtOAc
  • Example 6A To acetone (200 ml) Example 6A (20 g, 97.72 mmol) was added a solution of 1,5-dibromopentane (67 g, 293.2 mmol), K 2 CO 3 (27 g, 195.4 mmol) And KI (1.62 g, 9.77 mmol). After the addition was completed, the mixed solution was heated at 80 ° C for 12 hours. After the completion of the reaction, the reaction mixture was filtered, EtOAcjjjjjjjjjjj 75%).
  • Example 4F Sodium hydride (10 mg, 0.4 mmol, 60% content) was added to a solution of Example 4F (40 mg, 0.2 mmol) in N,N-dimethylformamide (10 ml) at 0 ° C
  • a solution of Example 6B 71 mg, 0.2 mmol of N,N-dimethylformamide (2 mL) was added.
  • the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate.
  • Example 7A (1.0 g, 6.05 mmol), 1,5-dibromopentane (1.39 g, 6.05 mmol), potassium carbonate (1.67 g, 12.11 mmol) and potassium iodide (0.1 g, 0.605 mmol) It was mixed with acetone (100 ml) and heated under reflux for 10 hours. Filtration, EtOAc (EtOAc) m.
  • Example 4F Sodium hydrogen (10 mg, 250 mmol, 60%) was added in portions to a solution of Example 4F (60 mg, 301.2 mmol) in N,N-dimethylformamide (1 mL) After stirring for 1.5 hours, a solution of Example 7B (114 mg, 361.4 mmol) of N,N-dimethylformamide (0.5 ml) was added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for 2 hr. In water (10 ml), EtOAc (3 mL,EtOAc) 30.7%).
  • Example 8A To a mixed solution of Example 8A (50 mg, 0.3 mmol) and water (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) The mixed solution was heated at 80 ° C for 1 hour, and the aqueous layer was extracted with ethyl acetate (m. 1 H-NMR (CDCl 3 , 400 MHz) ⁇ 7.52-7.66 (m, 1H), 6.68-6.87 (m, 2H), 4.12-4.30 (m, 2H), 2.78-3.07 (m, 4H), 1.27- 1.41 (m, 3H).
  • Example 8B To a mixed solution of Example 8B (80 mg, 0.4 mmol) and acetone (5.0 mL) was added 1,5-dibromopentane (288 mg, 1.26 mmol, 3.0 eq.), potassium carbonate (578 mg, 4.18) Millimol, 10 equivalents) and potassium iodide (7 mg, 0.04 mmol, 0.1 eq.) were heated at 80 ° C for 5 hours. After the reaction mixture was filtered, EtOAcjjjjjjjjjj LCMS (ESI) m/z:
  • Example 9A To a solution of Example 9A (80 mg, 0.25 mmol), 1-ethylpyrazole-4-boronic acid succinate (55 mg, 0.25 mmol) and sodium carbonate (53 mg, The catalyst Pd(dppf)Cl 2 (9 mg, 12.4 ⁇ mol) was added to a mixed solution of 0.5 mmol of 1,4-dioxane (3 ml) and water (0.5 ml), and stirred at 80 ° C. After a few hours, water (10 ml), EtOAc (EtOAc m. White solid, 26 mg, yield 31%).
  • Pd(dppf)Cl 2 9 mg, 12.4 ⁇ mol
  • Example 10A To a solution of Example 10A (3 g, 19.57 mmol) in EtOAc (10 mL). After the addition was completed, the mixed solution was heated at 60 ° C for 1 hour. The reaction mixture was cooled to EtOAc.
  • LCMS m.
  • Example 10B To a solution of Example 10B (10 g, 52.58 mmol) of N,N-dimethylformamide (100 ml), EtOAc (3.26 g, 105.15 mmol) and 1,5-dibromopentane (36.27) Gram, 157.73 mmol). After the mixture was stirred at 10 ° C for 12 hours, the mixture was evaporated. EtOAcjjjjjjjjjjjj The title compound (white solid, 10 g, yield 56%).
  • Example 11B To Example 11B (1 g, 450 mmol) was added 10 mL of a solution of hydrogen bromide. The mixed solution was heated at 110 ° C for 24 hours. After cooling, the reaction mixture was evaporated.
  • Example 6A To a mixture of Example 6A (1 g, 4.89 mmol), potassium carbonate (1.35 g, 9.77 mmol) and potassium iodide (810 mg, 4.89 mmol) in acetone (15 mL) -Bromoethoxy)ethane (3.4 g, 14.66 mmol). After the mixture was stirred at 70 ° C for 3 hours, it was evaporated to dryness.
  • Example 7A A mixture of Example 7A (4.98 g, 30.17 mmol), Example 14A (11.7 g, 27.43 mmol), EtOAc (EtOAc) Ethyl acetate (50 ml) and water (50 ml) were evaporated. EtOAc (EtOAc) Purification gave the title compound (EtOAc m.
  • Example 16A (80 mg, 0.16 mmol), tert-butyl carbamate (74 mg, 0.63 mmol) and cesium carbonate (103 mg, 0.32 mmol) of dioxane/N, N under N2.
  • dimethylformamide 1.5 ml / 0.5 ml
  • Pd 2 (dba) 3 (20 mg, 0.03 mmol
  • Xant-Phos (10 mg, 0.03 mmol) were added, and the mixture was added after the addition.
  • the solution was stirred at 110 ° C for 16 hours. After the solvent was removed in vacuo, EtOAc m. .
  • Example 4E Sodium hydrogen (93 mg, 2.32 mmol) was added to a solution of Example 4E (271 mg, 1.16 mmol) of N, N-dimethylformamide. After stirring at 0<0>C for 0.5 h, EtOAc (EtOAc &lt The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 12 hours.
  • 1,5-Pentanediol 60 g, 0.57 mol
  • 3,4-dihydropyran 48.5 g, 0.57 mol
  • p-toluenesulfonic acid 50 mg
  • a potassium carbonate solution 200 ml
  • ethyl acetate 150 ml ⁇ 3
  • the combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated.
  • Example 19A 60 g, EtOAc.
  • Example 19B (7.5 g, 40.27 mmol), EtOAc (EtOAc:EtOAc.
  • Dichloromethane 50 ml
  • water 50 ml
  • the mixture was adjusted to pH 6 with dilute aqueous hydrochloric acid and the aqueous layer was extracted with dichloromethane (100 ml ⁇ 3).
  • Example 19C To a solution of Example 19C (2.5 g, 6.03 mmol) elute The reaction was carried out at 50 ° C for 3 hours. The solvent was evaporated to dryness EtOAc EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Triethylphosphine (420 mg, 1.6 mmol) was slowly added to a mixture of Example 19E (500 mg, 1.6 mmol), tetrabromide (3.4 g, 10.3 mmol) in tetrahydrofuran (5 mL). The mixture was reacted at 60 ° C for 1 hour.
  • Example 19B (5.0 g, 29 mmol), 5'-bromo-2'-hydroxyacetophenone (6.37 g, 29 mmol) and piperidine (2.0 mL) were combined in ethanol (150 mL). After refluxing for 4 hours, the title compound was evaporated.
  • N-butyllithium (2.5 moles per liter, 1.8 milliliters, 4.6 millimoles) was slowly added dropwise to a solution of Example 20C (600 mg, 2.1 mmol) in anhydrous tetrahydrofuran (10.0 mL). ), continue to stir for 2 hours after the addition.
  • the reaction solution was again lowered to -78 ° C, and N,N-dimethylformamide (380 mg, 5.2 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight.
  • Example 21A To a solution of Example 21A (70 mg, 0.32 mmol) in water (2.0 mL), EtOAc (EtOAc, EtOAc. After heating for 3 hours, the reaction was stopped. The aqueous phase was extracted with ethyl acetate (5.0 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated.
  • Example 2 The product of Example 2 was resolved using SFC to obtain two chiral isomers.
  • the conditions used for the split are as follows:
  • Example 22a is the first isomer with a retention time of 2.80 minutes;
  • Example 22b is the second isomer with a retention time of 4.04 minutes.
  • Example 23A (1.0 g, 6.1 mmol), 1,5-dibromopentane (1.4 g, 6.1 mmol), potassium carbonate (1.67 g, 12.1 mmol) and potassium iodide (0.1 g, 0.61 mmol)
  • the acetone (100 ml) solution was heated to reflux for 10 hours.
  • Example 4E 100 mg, 428 ⁇ mol
  • N,N-dimethylformamide 3 mL
  • EtOAc EtOAc
  • Example 23C (80 mg, 171.3 micromoles), tert-butyl carbamate (120 mg, 1.0 mmol) and Cs 2 CO 3 (112 mg, 343 ⁇ mol) of dioxane and N under N2.
  • Pd 2 (dba) 3 (30 mg, 33 ⁇ mol) and Xant-Phos (15 mg, 38 ⁇ mol)
  • N-dimethylformamide 3 ml
  • 1 ml N-dimethylformamide
  • Example 27A 120 mg, 0.24 mmol in N,N-dimethylformamide (1 mL), EtOAc ( 159 mg, 171 mg, 1.5 mmol). Pd 2 (dba) 3 (8.6 mg, 20 mmol), Xantphos (11.7 mg, 20 mmol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated.
  • Example 8B A mixed solution of Example 8B (2.5 g, 13.1 mmol), 14A (6.1 g, 14.4 mmol) and potassium carbonate (3.6 g, 26.1 mmol) in acetonitrile (50 ml) was reacted at 80 ° C for 16 hours. Ethyl acetate (50 ml) and water (50 ml) were evaporated. The title compound (colorless liquid, 2.5 g, 39% yield).
  • Example 4E Slowly add sodium hydrogen (673 mg, 16.8 mmol) to a mixture of Example 4E (1.3 g, 4.8 mmol) of N,N-dimethylformamide (40 ml) at 0 ° C.
  • a mixture of Example 29A (2.5 g, 5.6 mmol) of N,N-dimethylformamide (40 ml) was obtained, and the mixture was reacted at 25 ° C for 12 hours.
  • Water (30 ml) was added to the reaction mixture, the aqueous layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj.
  • the title compound (yellow liquid, 2.1 g, 66% yield).
  • Example 29C by chiral separation (AD-H_3UM_3_60_3 ml_5MIN, Column: Chiralpak AD-350*4.6 mm ID, 3um mobile phase: 60% methanol (0.05% DEA) - CO 2 flow rate: 3 ml/min; wavelength: 220 nm; peak time: 1.334 min, 1.823 min) gave the title compound.
  • Example 30C 1.0 g, 2.3 mmol
  • EtOAc EtOAc
  • Example 31A (300 mg, 1.34 mmol) was added dropwise to a solution of lithium tetrahydroaluminum (102 mg, 2.68 mmol) in tetrahydrofuran (3 mL) at 0 ° C. Stir for 3 hours. Water (0.5 ml) and a 10% sodium hydroxide solution (0.5 ml) were added to the reaction mixture.
  • Example 31B To a solution of Example 31B (160 mg, 1.1 mmol), triphenylphosphine (1.79 g, 6.8 mmol) in THF (5 mL) After the addition was completed, the mixed solution was stirred at 60 ° C for 3 hours. Filtration, the filter cake was washed with EtOAc (EtOAc (EtOAc) (EtOAc) .
  • EtOAc EtOAc
  • Example 30C The preparation method of this example is referred to Example 30C.
  • Example 32C 550 mg, 2.5 mmol of N,N-dimethylformamide (8 mL). After stirring for 0.5 hours, a solution of 4-((5-bromophenyl)pentyl)benzaldehyde (671 mg, 2.5 mmol) in N,N-dimethylformamide (19 ml) was added dropwise. After stirring at 0 ° C for 0.5 hour, the reaction was terminated by TLC. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. The title compound (white solid, 400 mg, 60%) was obtained.
  • EtOAc EtOAc
  • Trifluoroacetic acid (5 ml) was added to a solution of EtOAc (EtOAc)EtOAc. After the end of the reaction, the reaction mixture was purified by EtOAc EtOAc (EtOAc) (Colorless oil, 2.66 g, yield 88%), used directly in the next step.
  • Example 32F (130 mg, 366 ⁇ mol), 4-bromo-2-methylpyridine (189 mg, 1.1 mmol), Cs 2 CO 3 (179 mg, 549 ⁇ mol), Pd 2 A solution of (dba) 3 (34 mg, 37 ⁇ mol) and Xant-phos (21 mg, 37 ⁇ mol) in dioxane (2 mL) was heated to 100 ° C for 6 hours. TLC shows complete consumption of raw materials. After the reaction mixture was cooled to room temperature, ethyl acetate (20 ml) was evaporated. The title compound (white solid, 100 mg, yield 61%).
  • Acetyl chloride was added to a solution of 4-bromo-2-aminopyridine (1.0 g, 5.8 mmol) and triethylamine (1.75 g, 17 mmol) in dichloromethane (50 mL). 454 mg, 5.8 mmol). The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated.
  • Example 32F (60 mg, 169 ⁇ mol), 4-bromo-2-fluoro-pyridine (30 mg, 169 ⁇ mol) and cesium carbonate (83 mg, 253 ⁇ mol) of dioxane under nitrogen.
  • Pd 2 (dba) 3 (15 mg, 17 ⁇ mol) and Xant-Phos (10 mg, 17 ⁇ mol) were added, and the mixture was stirred and heated to 100 ° C for 4 hours. After the TLC detection reaction was completed, the solvent was concentrated and evaporated. Water (20 ml) was added, and EtOAc (EtOAc m. The title compound (white solid, 70 mg, 92%).
  • Example 39 To a solution of Example 39 (20 mg, 44 ⁇ mol) and 2-aminoethanol (27 mg, 444 ⁇ mol) in dimethyl sulfoxide (0.5 mL) was added triethylamine (27 mg, 266). Micromolar). The mixed solution was reacted at 100 ° C for 2 hours. After the reaction was completed by EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated.
  • EtOAc EtOAc
  • Example 32F 50 mg, 141 ⁇ mol
  • 4-fluorobenzonitrile 17 mg, 141 ⁇ mol
  • N,N-dimethylimide 1 mL
  • Potassium carbonate 39 mg, 281 ⁇ mol
  • the combined organic layers were dried with sodium sulfate, filtered and evaporated.
  • Example 32B Sodium hydrogen (17 mg, 428 micromoles) was added to a solution of Example 32B (100 mg, 428. After 1 hour, the mixed solution was added to a solution of 1,5-dibromopentane (98 mg, 428 ⁇ mol) in DMF (4 ml), and the mixture was stirred at 10 ° C for 10 hr. The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Purification of the title compound (yield: 50 mg, 38% yield).
  • Example 45A 100 mg, 269 ⁇ mol
  • Example 8B 52 mg, 269 ⁇ mol
  • N,N-dimethylformamide 1 mL
  • 808 micromolar 808 micromolar
  • the reaction mixture was stirred at 80 ° C for 10 hr.
  • EtOAc EtOAc
  • the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Example 45C (550 mg, 1.4 mmol), 4-bromo 2-aminopyridine (499 mg, 2.9 mmol), potassium carbonate (498 mg, 3.6 mmol), 8-hydroxyquinoline 209 mg, 1.4 mmol, (1R, 2R)-cyclohexanediamine (165 mg, 1.4 mmol) and cuprous iodide (275 mg, 1.4 mmol) in DMF (10 mL) at 120 ° C Heat for 10 hours. After completion of the reaction, water was added and the aqueous phase was extracted with ethyl acetate (10 ml).
  • Example 48A To a solution of Example 48A (50 mg, 98 ⁇ mol) in dioxane (1 mL) was added EtOAc EtOAc (EtOAc, EtOAc. Molar), Pd 2 (dba) 3 (9 mg, 9.8 ⁇ mol) and Xant-phos (6 mg, 10 ⁇ mol). The mixture was reacted at 110 ° C for 10 hours. TLC showed the reaction was quenched with EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate, filtered and evaporated.
  • EtOAc EtOAc EtOAc, EtOAc. Molar
  • Pd 2 (dba) 3 9 mg, 9.8 ⁇ mol
  • Xant-phos 6 mg, 10 ⁇ mol
  • EtOAc EtOAc
  • Example 4E Sodium hydrogen (1.0 g, 27 mmol) was added to a solution of Example 4E (4.0 g, 17 mmol) in N,N-dimethylformamide (140 ml) at 10 ° C. The reaction was stirred for 1 hour. While maintaining this temperature, a solution of 1,5-dibromopentane (3.9 g, 17 mmol) in N,N-dimethylformamide (40 ml) was added dropwise, and then the reaction was continued for 1 hour. After the reaction was completed by thin layer chromatography, the reaction mixture was poured into ice water (100 ml) and ethyl acetate (100 ml).
  • Example 52B To a solution of Example 52B (110 mg, 0.25 mmol) of N,N-dimethylformamide (2 mL), EtOAc (EtOAc) Mg, 0.15 mmol). After the reaction was stirred at 50 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated. The combined organic phases were dried with EtOAc EtOAc. LCMS (ESI) m/z: 450 (21.
  • Example 52C To a solution of Example 52C (50 mg, 0.1 mmol) of N,N-dimethylformamide (1.5 ml), EtOAc (EtOAc, EtOAc, 23 mg, 0.2 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (19 mg, 20 ⁇ mol), Xantphos (12 mg, 20 ⁇ mol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated.
  • EtOAc EtOAc, 23 mg, 0.2 mmol
  • Example 55B To a solution of Example 55B (60 mg, 0.13 mmol),jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 18 mg, 0.15 mmol). After replacing the nitrogen, Pd 2 (dba) 3 (22 mg, 24 ⁇ mol), Xantphos (14 mg, 24 ⁇ mol) was added under nitrogen. After the reaction was stirred at 110 ° C for 15 hours, the reaction was quenched with water and the aqueous layer was evaporated.
  • Example 52A (346 mg, 998 ⁇ mol), Example 56A (163 mg, 978 ⁇ mol) and potassium carbonate (276 mg, 2.0 mmol), potassium iodide (17 mg, 100 ⁇ mol) in acetone (5 ml) Heating to 70 ° C, reaction for 3 hours. Thin layer chromatography showed that the raw materials have been completely consumed. The reaction solution was cooled to room temperature, filtered, and evaporated to dryness.
  • Example 52A To a solution of Example 52A (2.0 g, 5.2 mmol) and 5-hydroxy-1-indolone (774 mg, 5.2 mmol) in acetone (30 mL) The reaction solution was heated to 70 ° C for 2 hours, and the starting material was completely reacted. The reaction mixture was cooled to EtOAc. The title compound (yellow solid, 1.3 g, 55% yield).
  • Example 57A 1.3 g, 2.9 mmol
  • hydroxyamine hydrochloride 603 mg, 8.7 mmol
  • the reaction mixture was concentrated, EtOAcjjjjjjjjjj ).
  • Example 59A (2.00 g, 7.35 mmol), bis-colonol borate (2.24 g, 8.82 mmol), potassium acetate (2.16 g, 22.05 mmol), Pd(dppf)Cl
  • a solution of 2 (537.80 mg, 735.00 ⁇ mol) in dioxane (5 ml) was heated to 50 ° C for 10 hours. The reaction solution was cooled to room temperature and then filtered, and the crude product was applied directly to the next.
  • Example 59B To a mixed solution of Example 59B (2.0 g, 6.6 mmol) of sodium hydroxide (2 mL, 2N) and THF (8 ml) was added hydrogen peroxide (2.3 g, 65.5 mmol). The mixed solution was stirred at 25 ° C for 10 minutes and then water (5.0 mL) was added. The mixed solution was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate (mjjjjjjjj .
  • Example 59D (102 mg, 199 ⁇ mol), tert-butyl carbamate (222 mg, 1.9 mmol), Pd 2 (dba) 3 (18 mg, 20 ⁇ mol) of dioxane (5.0 ml) Xantphos (23 mg, 40 micromoles) and potassium carbonate (83 mg, 599 micromoles) were added to the solution.
  • Example 60 The preparation method of this example is referred to Example 60.

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Abstract

L'invention concerne un nouveau dérivé 1,2,5-thiadiazolidine-1,1-dioxyde anti-entérovirus 71 (EV71), ou un sel pharmaceutiquement acceptable de celui-ci, et plus spécifiquement un composé représenté par la formule (II) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2015/077043 2014-04-28 2015-04-21 Dérivé de thiadiazolidine anti-entérovirus 71 WO2015165340A1 (fr)

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US15/307,710 US9988361B2 (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
ES15786304T ES2841418T3 (es) 2014-04-28 2015-04-21 Derivado de tiadiazolidina como anti-enterovirus 71
CN201580011272.4A CN106661009B (zh) 2014-04-28 2015-04-21 抗肠病毒71噻二唑烷衍生物
JP2016565011A JP6389531B2 (ja) 2014-04-28 2015-04-21 抗エンテロウイルス７１チアジアゾリジン誘導体
KR1020187016595A KR101957178B1 (ko) 2014-04-28 2015-04-21 항엔테로바이러스71 티아디아졸리딘 유도체
SG11201608710TA SG11201608710TA (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
KR1020167033211A KR20160147010A (ko) 2014-04-28 2015-04-21 항엔테로바이러스71 티아디아졸리딘 유도체
DK15786304.4T DK3138840T3 (da) 2014-04-28 2015-04-21 Thiadiazolidin-derivat som anti-enterovirus 71
EP15786304.4A EP3138840B1 (fr) 2014-04-28 2015-04-21 Dérivé de thiadiazolidine comme anti-entérovirus 71

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CN201410176161 2014-04-28
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CN201410543064.6A CN105085512A (zh) 2014-04-28 2014-10-14 抗肠病毒71噻二唑烷衍生物
CN201410543064.6 2014-10-14
CN201510182757.1 2015-04-16
CN201510182757 2015-04-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3257851A4 (fr) * 2015-10-26 2018-09-19 Jiangsu Kanion Pharmaceutical Co., Ltd. Forme saline et forme cristalline de 1,2,5-thiadiazolidine-1,1-dioxyde, leur procédé de préparation et leur intermédiaire
WO2022012152A1 (fr) * 2020-07-17 2022-01-20 江苏康缘药业股份有限公司 Composition pharmaceutique et sa méthode de préparation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501568A1 (fr) * 1991-02-27 1992-09-02 MERCK SHARP & DOHME LTD. Dérivés de sulfamide cyclique substitué
US6706739B2 (en) * 2001-08-21 2004-03-16 National Health Research Institute Imidazolidinone compounds
US20040116476A1 (en) * 2002-07-09 2004-06-17 Jyh-Haur Chern Imidazolidinone compounds
WO2012134233A2 (fr) * 2011-03-31 2012-10-04 한국화학연구원 Dérivé de sulfamide possédant un groupe adamantyle et un sel pharmaceutiquement acceptable de celui-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501568A1 (fr) * 1991-02-27 1992-09-02 MERCK SHARP & DOHME LTD. Dérivés de sulfamide cyclique substitué
US6706739B2 (en) * 2001-08-21 2004-03-16 National Health Research Institute Imidazolidinone compounds
US20040116476A1 (en) * 2002-07-09 2004-06-17 Jyh-Haur Chern Imidazolidinone compounds
WO2012134233A2 (fr) * 2011-03-31 2012-10-04 한국화학연구원 Dérivé de sulfamide possédant un groupe adamantyle et un sel pharmaceutiquement acceptable de celui-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HOLMES, IAN P. ET AL.: "The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure", BIOORGANIC & MEDICAL CHEMISTRY LETTERS, vol. 20, no. 6, 25 January 2010 (2010-01-25), pages 2013 - 2016, XP027546795, ISSN: 0960-894x *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3257851A4 (fr) * 2015-10-26 2018-09-19 Jiangsu Kanion Pharmaceutical Co., Ltd. Forme saline et forme cristalline de 1,2,5-thiadiazolidine-1,1-dioxyde, leur procédé de préparation et leur intermédiaire
US10227339B2 (en) * 2015-10-26 2019-03-12 Jiangsu Kanion pharmaceutical CO. LTD Salt form and crystal form of 1,2,5-thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate
WO2022012152A1 (fr) * 2020-07-17 2022-01-20 江苏康缘药业股份有限公司 Composition pharmaceutique et sa méthode de préparation
EP4159200A4 (fr) * 2020-07-17 2024-07-17 Jiangsu Kanion Pharmaceutical Co Ltd Composition pharmaceutique et sa méthode de préparation

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